Basics
Description
- Defined as the appearance of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys
- Normal puberty occurs between age 8 and 14 years in girls and 9 and 14 years in boys (1,2).
- There are three types:
- Gonadotropin-dependent precocious puberty (GDPP) or central precocious puberty. Manifests secondary sexual characteristics in harmony such as bilateral breasts or testicular enlargement
- Gonadotropin-independent precocious puberty (GIPP) or peripheral precocious puberty. Does not manifest secondary sexual characteristics in harmony. It presents a clinical picture of incomplete puberty.
- Incomplete precocious puberty such as premature, adrenarche, and thelarche
Epidemiology
- More prevalent in African American children compared to White children
- Attention to racial differences is advised because African American girls normally develop secondary sexual characteristics at an earlier age than White girls.
- It is 10 times more common in girls than in boys.
- 80 " 90% of affected girls have idiopathic central precocious puberty (1,3).
Incidence
Estimated incidence of 0.01 " 0.05% per year in the United States (1)
Prevalence
In a population-based Danish study from 1993 to 2001, it was found that 0.2% of Danish girls and <0.05% of Danish boys were affected by some type of precocious puberty (3).
Etiology and Pathophysiology
- GDPP (4)
- Caused either by a central dysregulation of the hypothalamic-pituitary-gonadal axis resulting in overproduction of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or by ectopic hormone production such as hCG by a neoplasm
- Characterized by pubertal levels of FSH and LH
- Affected individuals have advanced bone age and short stature due to premature epiphyseal closure.
- Different causes include the following:
- Idiopathic central precocious puberty is the most common type.
- CNS lesions such as glioma, astrocytoma, hypothalamic hamartoma, and arachnoid cysts
- Congenital CNS anomaly such as hydrocephalus
- Infection such as encephalitis and meningitis
- Trauma
- CNS irradiation
- Primary hypothyroidism
- Gain-of-function mutation of the GPR54 protein, which is part of an essential signaling complex for the initiation of puberty
- GIPP (1)[B]
- Caused by excess secretion of androgens or estrogens produced from the gonads or adrenal glands or from exogenous sources
- FSH and LH levels are in the prepubertal range.
- Causes include the following:
- Girls
- Ovarian tumors such as Leydig cell tumors or granulosa cell tumors
- Ovarian cyst
- Boys
- Germ cell tumors secreting hCG
- Leydig cell tumors
- Familial male-limited precocious puberty or testotoxicosis caused by an activation mutation of the LH-receptor gene
- Both boys and girls
- Adrenal androgen production due to adrenocorticotropic hormone (ACTH) stimulation: congenital adrenal hyperplasia, 21-hydroxylase deficiency, 11- ²-hydroxylase deficiency
- McCune-Albright syndrome: a triad of precocious puberty, cafe-au-lait skin pigmentation, and fibrous dysplasia of the bone
- Excess exogenous estrogen exposure from creams, sprays, or ointments
- Incomplete precocious puberty (1)
- A variant of normal puberty
- Presents with early development of secondary sexual characteristics
- Premature thelarche
- Can occur in two peaks: during the first 2 years of life and between ages 6 and 8 years
- More common in Black and Hispanic children
- 14 " 20% of children affected can develop true precocious puberty.
- Characterized by
- Development of isolated unilateral or bilateral breasts
- Absence of other sexual characteristics
- Normal linear growth and normal bone age
- Sex hormones level are in the prepubertal range.
- Premature adrenarche
- Characterized by the appearance of pubic and/or axillary hair, acne, and adult body odor before the age of 8 years in girls and 9 years in boys
- Normal linear growth and bone age
- Common in girls and individuals with insulin resistance and obesity
- 20% of girls affected can develop polycystic ovarian syndrome as adults.
- Most cases are idiopathic but may be caused by congenital adrenal hyperplasia, 21-hydroxylase deficiency, Cushing disease, dehydroepiandrosterone-sulfate (DHEA-S) deficiency, autonomous endogenous or exogenous excess.
General Prevention
Precocious puberty is not preventable, but early detection is helpful, so the following steps are recommended:
- Careful growth chart review
- Thorough physical exam for early signs of puberty
- Anticipatory guidance in late childhood should include normal pubertal development.
Diagnosis
Any child with secondary sexual characteristics before the age of 8 years in girls and before the age of 9 years in boys should be evaluated (4)[B].
History
- Review past medical history, social history, and onset of puberty in family members.
- Review features of puberty present, rate of progression, and duration.
- Review growth charts for linear growth velocity.
- Presence of exogenous sources of sex steroids in the home
Physical Exam
- Measurement of height, weight, and height velocity (cm/year)
- Funduscopic exam and visual acuity test for possible CNS mass effect
- Complete neurologic exam to assess for CNS pathology
- Skin exam for cafe-au-lait spots (McCune-Albright syndrome)
- Tanner stage breasts and pubic hair in girls
- Measure testicular volume and penile size (3).
Differential Diagnosis
- Benign gynecomastia of adolescence
- CNS and pituitary lesions
- Exogenous sex hormones
- Adrenal hyperplasia
- Polycystic ovarian syndrome
- Ovarian tumor
- Adrenal tumor
- Cushing syndrome
Diagnostic Tests & Interpretation
Initial Tests (lab, imaging)
- Assess bone age of any child who presents with early secondary sexual characteristics (2)[A]. Accelerated bone age present in GDPP and GIPP but not in incomplete precocious puberty.
- Measure basal LH level and FSH level after gonadotropin-releasing hormone (GnRH) administration, which will differentiate between GDDP and GIPP.
- GDPP: LH and FSH levels are at pubertal levels, which will increase with administration of GnRH (1)[B],(2)[A]. Additional testing once the diagnosis of GDDP is made might include estradiol, testosterone, thyroid function tests, and MRI of the brain for identifiable CNS causes.
- GIPP: LH and FSH are at prepubertal range and will not respond to GnRH agonist. Additional testing to identify peripheral causes might include testosterone, estradiol, LH, FSH, dehydroepiandrosterone (DHEA), DHEA-S, 17-hydroxyprogresterone, hCG (in boys), and abdominal and pelvic ultrasound in girls for evaluation of ovarian cyst or tumor. Testicular ultrasound in boys to evaluate for possible Leydig cell tumor
- Premature thelarche: Normal levels of gonadotropins and estradiol, unremarkable pelvic ultrasound
- Premature adrenarche: Prepubertal range LH and FSH and will not respond to GnRH agonist.
Treatment
General Measures
- GDPP: The primary reason to treat is to prevent early epiphyseal closure and reduction of adult height.
- Good candidates are those who present at a younger age with rapidly progressing skeletal age compared to height age.
- Recommended to follow progression for 3 " 6 months in children who present with slow progression of puberty and height velocity before considering treatment (1)[B].
- Final height may increase 8 " 12 cm.
Medication
First Line
- GDPP: GnRH agonists such as leuprolide or triptorelin are the drugs of choice (5)[A],(6)[B].
- Treatment can be discontinued by age 11 years in girls and age 12 years in boys.
- Puberty returns on average 16 months after discontinuation of GnRH agonist.
- GIPP: Treat underlying conditions. It does not respond to GnRH agonists (1)[B].
- Incomplete precocious puberty: No therapy is required, but children should be monitored closely and reassurance should be given to patient and family (1)[B].
Issues for Referral
- Refer to endocrinologist for management of GDDP.
- Refer to neurologist for underlying intracranial processes.
Ongoing Care
Follow-up Recommendations
GDPP
- Evaluate every 3 " 6 months to assess pubertal growth and development and height velocity to detect abnormal growth spurt (1)[B].
- Measure bone age every 6 " 12 months with x-ray of epiphyseal growth plate of the hand.
- May also measure LH and sex steroids 2 months after the start of therapy or after changing dose, which should be in the prepubertal levels
- Adequate treatment should stop breast, testicular, phallus, and pubic hair development and should slow rate of height velocity and bone age maturation.
Prognosis
- Treatment reduces height velocity and children may achieve predicted height.
- May reduce psychosocial stressors associated with precocious puberty
Complications
- Short stature
- Psychosocial stressors associated with early onset of puberty
References
1.Chauhan A, Grissom M. Disorders of childhood growth and development: precocious puberty. FP Essent. 2013;410:25 " 31.
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2.Huffman GB. Reassessing the age limit of precocious puberty in girls. Am Fam Physician. 2000;61(6):1850 " 1852.3.Teilmann G, Pedersen CB, Jensen TK, et al. Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics. 2005;116(6):1323 " 1328.
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4.Papadimitriou A, Beri D, Tsialla A, et al. Early growth acceleration in girls with idiopathic precocious puberty. J Pediatr. 2006;149(1):43 " 46.
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5.Lee PA, Klein K, Mauras N, et al. 36-month treatment experience of two doses of leuprolide acetate 3-month depot for children with central precocious puberty. J Clin Endocrinol Metab. 2014;99(9):3153 " 3159.
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6.Bertelloni S, Baroncelli GI. Current pharmacotherapy of central precocious puberty by GnRH analogs: certainties and uncertainties. Expert Opin Pharmacother. 2013;14(12):1627 " 1639.
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Codes
ICD09
- 259.1 Precocious sexual development and puberty, not elsewhere classified
- 253.1 Other and unspecified anterior pituitary hyperfunction
ICD10
- E30.1 Precocious puberty
- E22.8 Other hyperfunction of pituitary gland
SNOMED
- 400179000 Precocious puberty (disorder)
- 237816004 Central precocious puberty (disorder)
- 19911007 Precocious female puberty (disorder)
- 190291004 Premature puberty due to hypothyroidism (disorder)
Clinical Pearls
- There are three types of precocious puberty: central, peripheral, and incomplete.
- Most common in girls and majority of cases represent idiopathic central precocious puberty
- GnRH agonists are the mainstay treatments for central precocious puberty; young individuals with rapidly progressing skeletal age will benefit the most.